Early repetitive pain in premature babies and may lead to permanent changes in brain development, with abnormal pain processing, increased anxiety, poor cognition, attention deficit disorder, and behavioral problems during adolescence or adulthood. Repetitive pain in newborn rats was associated with increased neuronal cell death in widely distributed cortical and subcortical areas. Following puberty, pain-exposed rats showed greater anxiety, hypervigilance, preattentional and cognitive deficits; thus mimicking the long-term behavioral outcomes of ex-preterm children. Understanding the mechanisms mediating these effects may lead to novel therapeutic measures and improve the cognitive and behavioral outcomes of premature birth. Aim 1: Determination of critical windows will test the hypothesis that repetitive pain is associated with increased neuronal cell death during the most sensitive developmental stage(s). Increased neuronal vulnerability may be developmentally regulated in different neuroanatomical areas, and will be correlated with cognitive and behavioral outcomes evaluated in adult rats. Aim 2: Investigation of cell death mechanisms will test the hypothesis that repetitive pain produces neuronal cell death by activating the signaling pathways leading to excitotoxicity via excitatory receptors. Pharmacological manipulations decreasing neuronal cell death will allow the development of novel therapeutic approaches, which will also be correlated with adult cognition and behavior. Aim 3: Assessment of pre-attentional processes in humans will test the hypothesis that abnormal regulation of arousal contributes to the cognitive deficits during adolescence or adulthood. A measure of arousal in humans, the P50 potential, will be compared between adolescents born preterm and matched term-born adolescents, and correlated with their performance of attentional tasks (Psychomotor Vigilance Test) and executive functions (Operant Test Battery), and with relative frontal lobe blood flow (Near Infrared Spectroscopy). The proposed research is designed to establish the Principal Investigator as an independent clinician scientist with the help of established mentoring under the auspices of the Center for Translational Neuroscience.